The Bcl-2 family of proteins function at an important checkpoint in apoptosis, and can be considered as arbiters deciding whether a cell lives or dies. The pro-death Bcl-2 family members includes Bak and Bax, which induce permeabilization of the mitochondrial membrane, and a collection of “BH3-only” proteins, such as Bim, Bid, and Noxa, that play different roles in inducing apoptosis. The canonical function of pro-survival members of the Bcl-2 family, including Bcl-xL, Bcl-2, Bcl-w, Mcl-1, and A1, is to antagonize apoptosis via heterodimeric interactions with the pro-death family members. Pro-survival Bcl-2 family members were identified as oncogenes, and these proteins are commonly overexpressed in human cancers as revealed by immunohistochemical and biochemical studies. Heterodimeric interactions between Bcl-2 family members are mediated by the helical amphipathic BH3 domain of the pro-death protein which binds to a surface cleft on the pro-survival protein.
One proposed therapeutic intervention in cancers focuses on inhibition of the heterodimeric interactions between family members via the binding of a BH3 peptide or a small molecule BH3 peptide mimic. Such inhibitors result in a decrease of sequestration of pro-death proteins by pro-survival proteins and restoration of apoptotic function to the cells. This strategy has been demonstrated successfully with several molecules including the small molecule ABT-737 and a conformationally constrained “stapled” BH3 peptide from the pro-death protein Bid, both of which exhibit cytotoxicity toward cancer cell lines and are able to reduce malignancies in xenograft models. Stapled peptides are helical peptides containing a sidechain-sidechain or backbone-sidechain crosslink that strongly biases the peptide toward a helical structure. Some classes of stapled peptides are able to cross cell membranes making them attractive as therapeutic lead molecules.